1) Field of the Invention
The present invention relates, in general, to a novel pharmaceutical composition containing biologically-active desmopressin, a vasopressin-based oligopeptide, in combination with a matrix buccal patch. More particularly, the invention is generally concerned with a buccally-administered solid pharmaceutical composition containing various doses of the active component dispersed in a buccal patch matrix. The invention allows reproducible, patient-friendly administration of the drug even when the patient has nasal congestion since one usual mode of administration of desmopressin is by nasal drops or spray. The composition is well-tolerated by patients of all ages, is just a effective as when administered by nasal drops or spray, provides prolonged and reliable action and can be stored at room temperature.
2) Description of the Related Art
It has long been recognized that natural vasopressin has useful biological effects, such as antidiuresis, vasoconstriction of visceral blood flow and release of hematological clotting factors. Its utility, however, is limited by its short half-life as well as by its well-known systemic pressor effect which includes cardio-toxicity.
A variety of analogs of vasopressin have been synthesized in an effort to modify the properties of vasopressin and provide products having increased pharmaceutical utility. For example, vasopressin has been modified by desamination of cysteine in position 1 and replacement of arginine by its D-isomer at position 8 to yield desmopressin, hereinafter also referred to as "dDAVP". Desmopressin, which is immune to enzymatic cleavage as of the 1-2 and 8-9 C--N bonds, exhibits prolonged antidiuretic action and virtually no pressor action or cardio-toxicity. For example, see U.S. Pat. Nos. 3,497,491 and 4,235,881. In further modifications, the disulfide bridge has been replaced with a thioether linkage (--CH.sub.2 S-- or --SCH.sub.2 --) or an ethylene (--(CH.sub.2 --) linkage. See also U.S. Pat. No. 3,980,631.
These vasopressin-based oligopeptides have been administered by a variety of routes and in combination with a variety of pharmaceutical carriers and additives. For example, dDAVP has been administered intranasally, subcutaneously, intravenously and intramuscularly in physiological saline at pH 4.
Various attempts have also been made to effectively orally administer vasopressin-based oligopeptides, particular dDAVP. It has been traditionally accepted that such peptides are cleaved into inactive fragments in the gastrointestinal tract with little nonapeptide adsorption taking place. dDAVP has been incorporated in gelatin-based sub-lingual lozenges (A. Grossman et al. "Two new modes of desmopressin (dDAVP) administration", British Medical Journal May 17, 1980, 1215). A difficulty with sub-lingual lozenge is the necessity for the patient to restrain tongue movement so as not to swallow it and the fact that the sub-lingual salivary glands are very productive of secretion, which carries off a variable and unknown quantity of the drug to be swallowed.
Additionally, dDAVP has been formulated into an orally administered (swallowed) composition in the form of a tablet with various fillers and inert constituents. The effective claimed dosage would appear to be 100-200.times.the intravenous level, but a difficulty remains with all swallowed forms of oligopeptides--there will be a considerable patient-to-patient and day-to-day (in one and the same patient) variation in how much of the dosage is enzymatically cleaved and what fraction remains intact to be absorbed. Furthermore, if any such tablet or lozenge is gelatin-based, the water content will limit stability--thus, both the lozenges and the oral tablets are stored at 3.degree.-8.degree. C. Finally, the time-of-onset of any activity from a dose presented in the gut will vary from patient to patient and, in the same patient, from day to day.
It is known in the art that various chemical compositions can be administered to patients through the mucous membranes of the body. Suppositories for rectal/vaginal administration are well known as well as nasal sprays and drops. More recently, the patent literature has disclosed the administration of pharmaceutically active chemicals through the mucous membrane of the mouth. For example, in U.S. Pat. No. 4,764,378 which issued Aug. 16, 1988 to A. D. Keith et al. there is disclosed a buccal drug dose form for the transmucosal administration of drugs using an erodible matrix. A wide variety of other issued patents, both foreign and domestic are cited therein which pertain directly or indirectly to buccal drug dose forms and their methods of use. However, while the claims therein include heat-sensitive active substances such as Desmopressin, Calcitonin and Growth Hormone, no data has been presented therein, or elsewhere, that oligopeptides and protein hormones can survive the about 40.degree. C. and one to two hour conditions used to include a drug in the given matrices. For Desmopressin no data has, to date, been presented at all. For Calcitonin and Growth Hormone the only data given are the approximate composition of the carrier mix and the statement that the latter hormones could be mixed therein, without mention of their chemical state and activity after mixing.
Accordingly, one or more of the following objects will be achieved by the practice of the present invention. It is an object of this invention to provide a pharmaceutical composition in the form of a buccal patch which contains biologically active desmopressin. A further object is to provide a composition in the form of a patch which is stable and can be stored at room temperature for extended periods of time. Another object of the present invention is to provide a method for administering desmopressin to a patient in need of such treatment and who at that time is experiencing nasal congestion. A still further object of the invention is to provide a method whereby desmopressin can be administered to a patient rapidly and in a manner which provides a sustained release of a continuous, even dosage over a period of time. These and other objects will readily become apparent to those skilled in the art in light of the teachings herein set forth.